气相色谱法测定比卡鲁胺中7种有机溶剂残留量

摘 要 目的： 建立顶空进样气相色谱法检测比卡鲁胺原料药中7种有机残留溶剂二氯甲烷、正己烷、四氢呋喃、乙醇、乙醚、丙酮和乙酸乙酯的方法。方法: 色谱柱为Agilent DB 624弹性石英毛细管柱（30.0 m×0.25 mm×1.4 μm）;进样口温度：200℃;氢火焰离子化检测器(FID)温度：250℃;柱温：程序升温,初始温度35℃,保持13 min,再以100℃/min的速率升至180℃,维持5 min;载气：氮气;流速：1.2 ml·min^-1。顶空进样,顶空平衡温度：90℃,顶空平衡时间：30 min;进样体积：1.0 ml;以二甲基亚砜为溶解介质,测定比卡鲁胺中7种溶剂的残留量。结果: 各被测溶剂均能良好分离,各溶剂峰面积与浓度均呈良好的线性关系,回收率均较为理想。 结论:该法适用于比卡鲁胺原料药中残留溶剂的测定。     

An Open,Randomised, Multicentre,Phase 3 Trial Comparing the Efficacy of Two Tamoxifen Schedules in Preventing Gynaecomastia Induced by Bicalutamide Monotherapy in Prostate Cancer Patients

Background

Bicalutamide monotherapy is a valuable option for prostate cancer (PCa) patients who wish to avoid the consequences of androgen deprivation; however, this treatment induces gynaecomastia and mastalgia in most patients. Tamoxifen is safe and effective in preventing breast events induced by bicalutamide monotherapy without affecting antitumor activity, but possible interference between bicalutamide and tamoxifen remains a matter of concern. To reduce the exposure to tamoxifen, we considered the putative advantages of weekly administration.

Objective

To compare the efficacy of two different schedules of tamoxifen in preventing breast events. Toxicity, prostate-specific antigen behaviour, and sexual-functioning scores were also evaluated.

Design, setting, and participants

This was a noninferiority trial. From December 2003 to February 2006, 80 patients with localised/locally advanced or biochemically recurrent PCa who were also candidates for bicalutamide single therapy were randomised to receive two different schedules of tamoxifen: daily (n = 41) and weekly (n = 39). Median follow-up was 24.2 mo.

Intervention

Daily bicalutamide (150 mg) plus daily tamoxifen 20 mg continuously (daily group) or the same but with tamoxifen at 20 mg weekly after the first 8 wk of daily treatment (weekly group). Three patients in the weekly group and one in the daily group were discontinued for adverse events.

Measurements

For gynaecomastia, we used ultrasonography. For mastalgia and sexual functioning, we used questionnaires.

Results and limitations

Gynaecomastia developed in 31.7% of patients in the daily group and in 74.4% of patients in the weekly group (p < 0.0001), and it was more severe in patients who switched to weekly tamoxifen (p = 0.001). Mastalgia occurred in 12.2% and 46.1% of patients, respectively (p = 0.001). There were no major differences among treatment schedules relative to sexual functioning scores and incidence and severity of adverse events. No differences between groups in PSA behaviour and disease progression have been detected so far.

Conclusions

This study demonstrated that tamoxifen 20 mg/wk is inferior to tamoxifen 20 mg/d in preventing the incidence and severity of bicalutamide-induced breast events. The safety and efficacy of tamoxifen at the common daily dose of 20 mg for the prophylaxis of bicalutamide-induced breast events were confirmed.     

Box–Behnken study design for optimization of bicalutamide-loaded nanostructured lipid carrier: stability assessment

Abstract

Bicalutamide (BCM) is an anti-androgen drug used to treat prostate cancer. In this study, nanostructured lipid carriers (NLCs) were chosen as a carrier for delivery of BCM using Box–Behnken (BB) design for optimizing various quality attributes such as particle size and entrapment efficiency which is very critical for efficient drug delivery and high therapeutic efficacy. Stability of formulated NLCs was assessed with respect to storage stability, pH stability, hemolysis, protein stability, serum protein stability and accelerated stability. Hot high-pressure homogenizer was utilized for formulation of BCM-loaded NLCs. In BB response surface methodology, total lipid, % liquid lipid and % soya lecithin was selected as independent variable and particle size and %EE as dependent variables. Scanning electron microscopy (SEM) was done for morphological study of NLCs. Differential scanning calorimeter and X-ray diffraction study were used to study crystalline and amorphous behavior. Analysis of design space showed that process was robust with the particle size less than 200?nm and EE up to 78%. Results of stability studies showed stability of carrier in various storage conditions and in different pH condition. From all the above study, it can be concluded that NLCs may be suitable carrier for the delivery of BCM with respect to stability and quality attributes.     

Survival benefit of early androgen receptor inhibitor therapy in locally advanced prostate cancer: Long-term follow-up of the SPCG-6 study

BackgroundThe optimal timing of endocrine therapy in non-metastatic prostate cancer (PCa) is still an issue of debate.MethodsA randomised, double-blind, parallel-group trial comparing bicalutamide 150 mg once daily with placebo in addition to standard care in patients with hormone-naïve, non-metastatic PCa. Kaplan–Meier analysis was used to estimate overall survival (OS) and multivariate Cox proportional hazard model was performed to analyse time-to-event (death).FindingsA total of 1218 patients were included into the Scandinavian Prostate Cancer Group (SPCG)-6 study of which 607 were randomised to receive bicalutamide in addition to their standard care and 611 to receive placebo. Median follow-up was 14.6 years. Overall, 866 (71.1%) patients died, 428 (70.5%) in the bicalutamide arm and 438 (71.7%) in the placebo arm, p = 0.87. Bicalutamide significantly improved OS in patient with locally advanced disease (hazard ratios (HR) = 0.77 (95% confidence interval (CI): 0.63–0.94, p = 0.01), regardless of baseline prostate-specific antigen (PSA), with a survival benefit which was apparent throughout the study period. In contrast, survival favoured randomisation to the placebo arm in patients with localised disease (HR = 1.19 (95% CI: 1.00–1.43), p = 0.056). However, a survival gain from bicalutamide therapy was present in patients with localised disease and a baseline PSA greater than 28 ng/mL at randomisation. In multivariate Cox proportional hazard model, only including patients managed on watchful waiting as their standard of care (n = 991) OS depended on age, World Health Organisation (WHO) grade, baseline PSA, clinical stage and randomised treatment.InterpretationThroughout the 14.6 year follow-up period the addition of early bicalutamide to standard of care resulted in a significant OS benefit in patients with locally advanced PCa. In contrast, patients with localised PCa and low PSA derived no survival benefit from early bicalutamide. The optimal timing for initiating bicalutamide in non-metastatic PCa patients is dependent on disease stage and baseline PSA.     

Combination of curcumin and bicalutamide enhanced the growth inhibition of androgen-independent prostate cancer cells through SAPK/JNK and MEK/ERK1/2-mediated targeting NF-κB/p65 and MUC1-C

Background

Prostate cancer is one of the most common malignancies in men. The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features, resulting in a poor outcome. However, the functional role for MUC1 C-terminal domain (MUC1-C) in androgen-independent prostate cancer occurrence and development has remained unclear.

Methods

Cell viability was measured by MTT assays. Western blot analysis was performed to measure the phosphorylation and protein expression of SAPK/JNK and ERK1/2, and MUC1-C, NF-κB subunit p65 and p50. Exogenous expression of MUC1-C, NF-κB subunit p65 was carried out by transient and electroporated transfection assays.

Results

We showed that curcumin inhibited the growth of androgen-independent prostate cancer cells and a synergy was observed in the presence of curcumin and bicalutamide, the androgen receptor antagonist. To further explore the potential mechanism underlining this, we found that curcumin increased the phosphorylation of ERK1/2 and SAPK/JNK, which was enhanced by bicalutamide. In addition, curcumin reduced the protein expression of MUC1-C and NF-κB subunit p65, which were abrogated in the presence of the inhibitors of MEK/ERK1/2 (PD98059) and SAPK/JNK (SP60015). A further reduction was observed in the combination of curcumin with bicalutamide. Moreover, while exogenous expression of MUC1-C had little effect on curcumin-reduced p65, the overexpression of p65 reversed the effect of curcumin on MUC1-C protein expression suggesting that p65 is upstream of MUC1-C. Intriguingly, we showed that exogenous expression of MUC1-C feedback diminished the effect of curcumin on phosphorylation of ERK1/2 and SAPK/JNK, and antagonized the effect of curcumin on cell growth.

Conclusion

Our results show that curcumin inhibits the growth of androgen-independent prostate cancer cells through ERK1/2- and SAPK/JNK-mediated inhibition of p65, followed by reducing expression of MUC1-C protein. More importantly, there are synergistic effects of curcumin and bicalutamide. The negative feedback regulatory loop of MUC1-C to ERK1/2 and SAPK/JNK further demonstrates the role of MUC1-C that contributes to the overall responses of curcumin. This study unveils the potential molecular mechanism by which combination of curcumin with bicalutamide enhances the growth inhibition of androgen-independent prostate cancer cells.     

A randomised,double-blind study comparing the addition of bicalutamide with or without dutasteride to GnRH analogue therapy in men with non-metastatic castrate-resistant prostate cancer

BackgroundBicalutamide blocks androgen action and is frequently used in men with non-metastatic, castration-resistant prostate cancer (CRPC). By reducing intracellular dihydrotestosterone, dutasteride (dual 5-alpha reductase inhibitor) could increase the effectiveness of bicalutamide in this setting. The objective of the study is therefore to prospectively evaluate dutasteride plus bicalutamide in men with asymptomatic, non-metastatic CRPC with rising prostate-specific antigen (PSA).MethodsProstate cancer patients with rising PSA whilst on first-line androgen deprivation therapy (ADT) were randomised (1:1) in a double-blind trial to receive bicalutamide 50 mg plus placebo or bicalutamide 50 mg plus dutasteride 3.5 mg once daily for 18 months.Randomisation was stratified by centre; treatment assignments were generated using GlaxoSmithKline’s RandAll System. Subjects who completed 18 months could participate in the 2-year extension. Central laboratory and study sites/monitors remained treatment-blinded.Primary end-point was time to disease progression (TDP) up to 42 months (defined as PSA progression from baseline or nadir, radiographic disease progression, death from prostate cancer or receipt of rescue medication).FindingsThere was no statistically significant difference in TDP in 127 men treated with bicalutamide/dutasteride (n = 62) compared with bicalutamide/placebo (n = 65) (hazard ratio (HR) = 0.94 [95% confidence interval (CI) 0.61, 1.46]; p = 0.79). The estimated median TDP was 425 days (95% CI 302, 858) in the bicalutamide/placebo group and 623 days (95% CI 369, 730) in the bicalutamide/dutasteride group. There was no statistically significant difference between the treatment groups for any secondary efficacy end-points, including time to treatment failure or PSA response. In the multivariate analysis, age, non-White race, higher baseline testosterone and lower baseline PSA were associated with longer TDP. Adverse events were comparable between treatment groups.InterpretationIn men with non-metastatic CRPC, adding dutasteride to bicalutamide did not significantly prolong TDP. Prospective data are provided concerning the common practice of using bicalutamide in this setting.     

比卡鲁胺胶囊对前列腺癌术后患者恢复效果的影响

目的观察比卡鲁胺胶囊对前列腺癌术后患者恢复效果的影响。方法选取2016年4月-2019年12月新疆生产建设兵团第十三师红星医院收治的前列腺癌患者80例,根据随机数字表法分为观察组和对照组,各40例。对照组患者接受前列腺癌手术去势治疗,观察组在对照组治疗基础上加用比卡鲁胺胶囊治疗。比较2组患者近期疗效,治疗前后前列腺特异性抗原(PSA)与血管内皮生长因子(VEGF)水平变化,生活质量改善情况及不良反应(性功能降低、骨骼疼痛、尿路梗阻、乳房发育、脊髓压迫)发生情况。结果治疗6个月后,观察组总有效率为97.50%,高于对照组的85.00%(χ²=3.914,P=0.048);治疗后2组患者PSA和VEGF水平均较治疗前明显降低,且观察组PSA和VEGF水平低于对照组(P均<0.01);观察组生活质量总改善率为97.50%,高于对照组的82.50%(χ²=5.000,P=0.025);观察组不良反应总发生率为20.00%,低于对照组的55.00%(χ²=10.453,P=0.001)。结论比卡鲁胺胶囊用于前列腺癌患者术后恢复效果显著,可快速改善患者临床症状,提高患者术后生活质量,降低了患者不良反应发生风险,值得临床推广应用。     

HPLC法测定比卡鲁胺含量

目的建立比卡鲁胺原料药高效液相色谱法的含量测定方法。方法色谱柱为Hypersil BDS-C18(200 mm×4.6 mm,5μm),流动相:甲醇-水(体积比60∶40);流速1.0 mL.m in-1,检测波长为270 nm,进样量20μL。结果比卡鲁胺在32.0~112.0μg.mL-1范围内呈良好线性关系,r=0.9998,最低检测限为8.3 ng。结论该方法专属性强,灵敏度高,重现性好,可作为比卡鲁胺原料药含量测定方法。     

比卡鲁胺联合化疗治疗去势抵抗性前列腺癌的临床分析

目的探讨晚期去势抵抗性前列腺癌安全、有效的治疗方法。方法以比卡鲁胺作为二线抗雄激素药物,联合多西紫杉醇加泼尼松化疗治疗26例去势抵抗性前列腺癌患者,观察疗效及毒副反应。结果 26例去势抵抗性前列腺癌患者25例有效,有效率为96.15%。最常见的毒副反应是骨髓抑制,可耐受。结论比卡鲁胺作为二线抗雄激素药物联合多西紫杉醇加泼尼松化疗治疗去势抵抗性前列腺癌的临床疗效明显,毒副反应轻,可作为晚期去势抵抗性前列腺癌的治疗策略。